US2021008018A1PendingUtilityA1
Deuterated analogs of d-beta-hydroxybutyric acid and uses thereof
Assignee: CONCERT PHARMACEUTICALS INCPriority: Mar 23, 2018Filed: Sep 21, 2020Published: Jan 14, 2021
Est. expiryMar 23, 2038(~11.6 yrs left)· nominal 20-yr term from priority
A61P 25/28A61P 25/16A61P 25/08A61P 25/00A61K 31/19A61K 9/0053C07B 2200/05C07C 69/675C07C 59/01
51
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
wherein each of the variables are defined herein, and pharmaceutically acceptable salts thereof, analogs and prodrugs thereof, pharmaceutical compositions thereof, and methods of use.
Claims
exact text as granted — not AI-modified1 . A pharmaceutical composition comprising a compound of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
each of Y 1a , Y 1b , Y 1c , Y 2 , Y 3a and Y 3b is independently H or D;
R 1 is H, D, —C(O)—C 1-6 alkyl, or
R 2 is H, D, —C 1-6 alkyl, —C 3-10 cycloalkyl, or
each of Y 4a , Y 4b , Y 5 , Y 6a , Y 6b , Y 7a , Y 7b and Y 8 , when present, is independently H or D; and
each of R 3 and R 4 , when present, is independently CH 3 or CD 3 ;
provided that at least one of Y 1a , Y 1b , Y 1c , Y 2 , Y 3a and Y 3b is D; and
further provided that when R 1 is H and R 2 is H, then at least one of Y 2 , Y 3a and Y 3b is D;
wherein each position designated specifically as deuterium has at least 50.1% incorporation of deuterium;
and a pharmaceutically acceptable carrier.
2 . The pharmaceutical composition of claim 1 , wherein the compound is a compound of Formula Ib:
or a pharmaceutically acceptable salt thereof, and wherein
each of Y 1a , Y 1b , Y 1c , Y 2 , Y 3a and Y 3b is independently H or D;
provided that at least one of Y 2 , Y 3a and Y 3b is D.
3 . The pharmaceutical composition of claim 1 , wherein the compound is a compound of Formula 2:
or a pharmaceutically acceptable salt thereof, wherein:
each Y 1 is the same and is H or D;
each of Y 2 , Y 3a and Y 3b is independently H or D;
each of Y 4a , Y 4b and Y 5 is independently H or D;
R 2 is H or D; and
R 3 is CH 3 or CD 3 ;
provided that at least one of Y 1 , Y 2 , Y 3a and Y 3b is D.
4 . The pharmaceutical composition of claim 1 , wherein the compound is a compound of Formula 3:
or a pharmaceutically acceptable salt thereof, wherein:
each Y 1 is the same and is H or D;
each of Y 2 , Y 3a and Y 3b is independently H or D;
each of Y 6a , Y 6b , Y 7a , Y 7b and Y 8 is independently H or D; and
R 4 is CH 3 or CD 3 ;
provided that at least one of Y 1 , Y 2 , Y 3a and Y 3b is D.
5 . The pharmaceutical composition of claim 1 , wherein the compound is a compound of Formula 4:
or a pharmaceutically acceptable salt thereof, wherein:
each Y 1 is the same and is H or D;
each of Y 2 , Y 3a and Y 3b is independently H or D;
each of Y 4a , Y 4b and Y 5 is independently H or D;
each of Y 6a , Y 6b , Y 7a , Y 7b and Y 8 is independently H or D;
R 3 is CH 3 or CD 3 ; and
R 4 is CH 3 or CD 3 ;
provided that at least one of Y 1 , Y 2 , Y 3a and Y 3b is D.
6 . The pharmaceutical composition of claim 1 , wherein Y 1a , Y 1b and Y 1c are the same and are each H or each D.
7 . The pharmaceutical composition of claim 1 , wherein Y 3a and Y 3b are the same and are each H or each D.
8 . The pharmaceutical composition of claim 1 , wherein Y 2 is D.
9 . The pharmaceutical composition of claim 1 , wherein Y 2 is H.
10 . The pharmaceutical composition of claim 1 , wherein each Y 1 is D.
11 . The pharmaceutical composition of claim 1 , wherein each Y 1 is H.
12 . The pharmaceutical composition of claim 1 , wherein Y 3a and Y 3b are each H.
13 . The pharmaceutical composition of claim 1 , wherein Y 3a and Y 3b are each D.
14 . The pharmaceutical composition of claim 2 , wherein Y 1a , Y 1b and Y 1c are the same, Y 2 is D, and the compound is selected from any one of the compounds set forth in the table below:
Each Y 1a ,
Compound #
Y 1b and Y 1c
Y 3a
Y 3b
100
H
H
H
101
H
H
D
102
D
H
H
103
D
D
H
104
H
D
D
105
D
D
D
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
15 . The pharmaceutical composition of claim 2 , wherein Y 1a , Y 1b and Y 1c are the same, Y 2 is H, and the compound is selected from any one of the compounds set forth in the table below:
Each Y 1a ,
Compound #
Y 1b and Y 1c
Y 3a
Y 3b
201
H
H
D
203
D
D
H
204
H
D
D
205
D
D
D
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
16 . The pharmaceutical composition of claim 3 , wherein each Y 1 is the same, Y 2 is D, Y 3a and Y 3b are the same; Y 4a and Y 4b are the same, R 2 is H, and the compound is selected from any one of the compounds set forth the table below:
Compound #
Each Y 1
Each Y 3a /Y 3b
Each Y 4a /Y 4b
Y 5
R 3
300
H
H
H
H
CH 3
301
D
H
H
H
CH 3
302
H
D
H
H
CH 3
303
H
H
D
H
CH 3
304
H
H
H
D
CH 3
305
H
H
H
H
CD 3
306
D
D
H
H
CH 3
307
D
H
D
H
CH 3
308
D
H
H
D
CH 3
309
D
H
H
H
CD 3
310
H
D
D
H
CH 3
311
H
D
H
D
CH 3
312
H
D
H
H
CD 3
313
H
H
D
D
CH 3
314
H
H
D
H
CD 3
315
H
H
H
D
CD 3
316
D
D
D
H
CH 3
317
D
D
H
D
CH 3
318
D
D
H
H
CD 3
319
D
H
D
D
CH 3
320
D
H
D
H
CD 3
321
D
H
H
D
CD 3
322
H
D
D
D
CH 3
323
H
D
D
H
CD 3
324
H
D
H
D
CD 3
325
H
H
D
D
CD 3
326
D
D
D
D
CH 3
327
D
D
D
H
CD 3
328
D
D
H
D
CD 3
329
D
H
D
D
CD 3
330
H
D
D
D
CD 3
331
D
D
D
D
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
17 . The pharmaceutical composition of claim 4 , wherein each Y 1 is the same; Y 2 is D; Y 3a and Y 3b are the same, Y 6a , Y 6b , Y 7a , and Y 7b are the same, and the compound is selected from any one of the compounds set forth the table below:
Each Y 6a /Y 6b
Compound #
Each Y 1
Each Y 3a /Y 3b
Y 7a /Y 7b
Y 8
R 4
500
H
H
H
H
CH 3
501
D
H
H
H
CH 3
502
H
D
H
H
CH 3
503
H
H
D
H
CH 3
504
H
H
H
D
CH 3
505
H
H
H
H
CD 3
506
D
D
H
H
CH 3
507
D
H
D
H
CH 3
508
D
H
H
D
CH 3
509
D
H
H
H
CD 3
510
H
D
D
H
CH 3
511
H
D
H
D
CH 3
512
H
D
H
H
CD 3
513
H
H
D
D
CH 3
514
H
H
D
H
CD 3
515
H
H
H
D
CD 3
516
D
D
D
H
CH 3
517
D
D
H
D
CH 3
518
D
D
H
H
CD 3
519
D
H
D
D
CH 3
520
D
H
D
H
CD 3
521
D
H
H
D
CD 3
522
H
D
D
D
CH 3
523
H
D
D
H
CD 3
524
H
D
H
D
CD 3
525
H
H
D
D
CD 3
526
D
D
D
D
CH 3
527
D
D
D
H
CD 3
528
D
D
H
D
CD 3
529
D
H
D
D
CD 3
530
H
D
D
D
CD 3
531
D
D
D
D
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
18 . The pharmaceutical composition of claim 1 , wherein each position designated specifically as deuterium has at least 90% incorporation of deuterium.
19 . The pharmaceutical composition of claim 1 , wherein each position designated specifically as deuterium has at least 95% incorporation of deuterium.
20 . The pharmaceutical composition of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
21 . The pharmaceutical composition of claim 1 , wherein the compound is at least about 90% stereomerically pure.
22 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is suitable for oral administration.
23 . A method of treating a disease or disorder that is responsive to increased brain-derived neurotrophic factor (BDNF), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of Y 1a , Y 1b , Y 1c , Y 2 , Y 3a and Y 3b is independently H or D;
R 1 is H, D, —C(O)—C 1-6 alkyl or
R 2 is H, D, —C 1-6 alkyl, —C 3-10 cycloalkyl, or
each of Y 4a , Y 4b , Y 5 , Y 6a , Y 6b , Y 7a , Y 7b and Y 8 , when present, is independently H or D;
each of R 3 and R 4 , when present, is CH 3 or CD 3 ;
provided that at least one of Y 1a , Y 1b , Y 1c , Y 2 , Y 3a and Y 3b is D;
wherein each position designated specifically as deuterium has at least 50.1% incorporation of deuterium;
and a pharmaceutically acceptable carrier.
24 . The method of claim 23 , wherein the disease or disorder is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, Rett syndrome, schizophrenia, major depressive disorder, major depressive disorder with mixed features, bipolar disorder, bipolar mania, bipolar depression, treatment-refractory depression, mild cognitive impairment, cognitive deficits in Parkinson's disease, cognitive deficits in depression, cognition deficits associated with Huntington's disease, subjective cognitive decline, age-related memory loss, a seizure disorder such as epilepsy, generalized anxiety disorder, post-traumatic stress disorder, traumatic brain injury, dementia including Lewy Body Dementia, obsessive-compulsive disorder, and eating disorders including anorexia nervosa and bulimia nervosa.
25 . A method of treating a disease or disorder that is responsive to increased brain-derived neurotrophic factor (BDNF), the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of claim 1 .
26 . The method of claim 25 , wherein the disease or disorder is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, Rett syndrome, schizophrenia, major depressive disorder, major depressive disorder with mixed features, bipolar disorder, bipolar mania, bipolar depression, treatment-refractory depression, mild cognitive impairment, cognitive deficits in Parkinson's disease, cognitive deficits in depression, cognition deficits associated with Huntington's disease, subjective cognitive decline, age-related memory loss, a seizure disorder such as epilepsy, generalized anxiety disorder, post-traumatic stress disorder, traumatic brain injury, dementia including Lewy Body Dementia, obsessive-compulsive disorder, and eating disorders including anorexia nervosa and bulimia nervosa.
27 . A compound of Formula IIIa:
or a pharmaceutically acceptable salt thereof, wherein:
each Z 1 is the same and is H or D;
each Z 2 is H or D;
each Z 3 is the same and is H or D;
each Z 4 is the same and is H or D;
R a is H or D; and
R b is H or D;
provided that at least one of Z 1 , Z 2 , Z 3 and Z 4 is D;
wherein each position designated specifically as deuterium has at least 50.1% incorporation of deuterium;
and a pharmaceutically acceptable carrier.Join the waitlist — get patent alerts
Track US2021008018A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.